Basically substituted 10,5 - (epoxymethano) - 10,11 - dihydro - 5h - dibenzo(a,d)cycloheptenes



United States Patent ()lhce 3,535,340 Patented Oct. 20, 1970 3,535,340 BASICALLY SUBSTITUTED 10,5 (EPOXY- METHANO) 10,11 DIHYDRO 5H DI- BENZO[a,d]CYCLOHEPTENES Thomas A. Dobson, St. Laurent, Quebec, and Martin A.

Davis, Montreal, Quebec, Canada, assignors to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Jan. 17, 1967, Ser. No. 609,788 Int. Cl. C07d 9/00 US. Cl. 260333 5 Claims ABSTRACT OF THE DISCLOSURE There are disclosed herein a number of ll-substituted 10,5-(epoxymethano) 10,1l-dihydro-SH-dibenzo[a,d] cycyloheptenes in which the substituent in position 11 is a dialkylamino group in which the alkyl groups are the same or different and contain from 16 carbon atoms each, the N-methylbenzylamino, the N-propylphenethylamine, the pyrrolidino, morpholino, piperidino, N'-methylpiperazino, or N-phenylpiperazino group. The intermediate S-methanol derivatives with the seven substituents in position 11 as listed above are also described. The compounds are useful as trichomonicidal and anti-convulsant agents, and methods for their use as well as a process of preparation are also disclosed.

This invention relates to novel chemical compounds having useful biological properties. In particular, this invention relates to novel 10,5-(epoxymethano)-10,1l-dihydro-5H-dibenzo[a,d] cycloheptenes of the following Formula I wherein R and R are the same or different and represent a lower alkyl group containing from 1-6 carbon atoms, or an aralkyl group containing from 7l0 carbon atoms such as, for example, the benzyl, phenethyl, or trimethoxybenzyl groups. In addition the grouping NR R may itself form part of a heterocycle containing from l2 hetero atoms and from 4-10 carbon atoms, such as, for example, the pyrrolidino, piperidino, morpholino or 4- substituted piperazino groups such as, for example, the N phenylpiperazino or N methylpiperazino groups. This invention also comprises the acid addition salts of the compounds of Formula I with pharmacologically ac ceptable acids such as, for example, sulfuric, hydrochloric, oxalic, maleic, or citric acids.

The compounds of Formula I are readily prepared from the corresponding 11-substituted-l0,5-(epoxymethano) 10,11 dihydro-5H-dibenzo[a,d]-cyclohepten-13- ones of Formula II wherein either R and R are as defined above or the grouping NR R forms part of a heterocycle as defined above. Such a compound of Formula II is treated with a complex alkali metal aluminium hydride to convert it to the corresponding l1-substituted-lO-hydroxy- 10,11 dihydro 5H-dibenzo[a,d]cycloheptene-S-methanol of Formula III wherein either R and R or the grouping NR R are as defined above. In its turn this compound is dehydrated with a mineral acid to give the corresponding compound of Formula I.

More specifically, a mixture of ll-substituted 10,5- (epoxy'methano) 10,11 dihydro-SH-dibenzo[a,d]cyclohepten-l3-one of Formula II wherein either R and R or the grouping NR R is as defined above, an inert solvent such as, for example, ether, tetrahydrofuran or dioxan and a complex alkali metal aluminium hydride conveniently lithium aluminium hydride is stirred and heated at a temperature within the range of 30l00 for a period of time of from one to twelve hours to give, after hydrolysis of the resulting complex with water, the corre* sponding 1 l-substituted-l 0-hydroxy-10,1 l-dihydro-SH-dibenzo[a,d]cyclohepten-S-methanol of Formula III. In its turn this compound is treated with a molar excess of a 10-50% aqueous solution of a mineral acid, preferably sulfuric acid, at a temperature within the range of 50- C. for a period of time of from one to six hours. The mixture is then rendered alkaline to liberate the corresponding compound of Formula I wherein either R and R or the grouping NR R are as defined above.

The compounds of this invention are active against Trichomonas vaginalis and are useful as trichomonicidal agents. As such they may be formulated with suitable excipents, such as, for example, starch or lactose, in the form of vaginal tablets or inserts containing from 50-250 mg. of the active ingredient and may be administered from one to three times per day. The compounds of this invention also possess anticonvulsant activity and are useful in treatment of certain disorders associated with convulsion. As such, they may be formulated with suitable excipients in the form of tablets or capsules containing from 75-300 mg. of the active ingredient and may be administered from one to several times per day.

The starting materials for the compounds of this invention, that is the 11-substituted-10,5-(epoxymethano)-10, 1l-dihydro-SH-dibenzo[a,d]cyclohepten-13-ones of Formula II wherein either R and R or the grouping NR R are as defined above are prepared as described in our c0- pending US. patent application S.N. 591,106, filed Nov. 1, 1966. In brief, one molar proportion of bromine is added to SH-dibenzo[a,d]cycloheptene-S-carboxamide, prepared as described by M.A. Davis et al. in J. Med. Chem. 7, 88 (1964) and the resulting dibromo compound is treated with boiling water or a boiling alkanol to give 11 bromo l0,5-(epoxymethano)-l0,ll-dihydro-SH-dibenzo[a,d]cyclohepten-13-one. This compound is then treated with a secondary amine of formula HNR R wherein either R or R or the grouping NR R are as defined above to give the corresponding compound of Formula II.

Geometrical isomers of the above-described compounds of Formula II are prepared by treating ll-bromo 10,5- (epoxymethano) 10,11 dihydro 5H dibenzo[a,d] cyclohepten-13-one with an aqueous alkali metal hydroxide solution to give, after processing, 10-11 epoxyl0,1l dihydro 5H dibenzo[a,d]cycloheptene-5-carboxylic acid. In its turn, this compound is treated with a molar excess of a secondary amine of formula HNR R wherein either R and R or the grouping NRR are as defined above, at a temperature within the range of TOO- C. in an inert solvent, such as, for example,

3 toluene, or xylene for a period of time of up to one day to give the desired geometrical isomers of the compounds of Formula II.

The following formulae and examples will illustrate this invention.

EXAMPLE 1 11-dimethylamino-10,5-(epoxymethano)-10,11-dihydro- 20 SH-dibenzo [a,d] cycloheptene A mixture of ll-dimethylamino 10,5 (epoxymethano)-10,11 dihydro SH dibenzo[a,d]cyclohepten-13- one (10.0 g.), anhydrous ether (500 ml.), and lithium 2 aluminum hydride (2.5 g.), is refluxed and stirred for 8 hours. The mixture is cooled and cautiously treated with water, filtered, and the solid residue is extracted with boiling methanol. The cooled extracts deposit crystals of ll-dimethylamine 1 hydroxy 10,11 dihydro-5H- dibenzo[a,d]cycloheptene-S-methanol with M.P. 208- 211 C.

A mixture of the above intermediate product (5.0 g.), water ml.), and sulfuric acid (10 ml.), is heated on the steam bath for 6 hours. The cooled mixture is rendered alkaline and then extracted with ether. Evaporation of the ethereal extracts gives the title product as an oil characterized by its nuclear magnetic resonance spectrum with maxima at 430, 321, 230-320 and 154 cps.

The hydrochloride salt is obtained by treating the above compound with either ethereal or methanolic hydrogen chloride. It is crystallized from ethanol-ether to M.P. 220-225 C.

EXAMPLE 2 1l-morpholino-10,5-(epoxymethano)-10,1l-dihydro- SH-dibenzo [a,d] cycloheptene A mixture of ll-morpholino 10,5 (epoxymethano)- 10,11 dihydro 5H dibenzo[a,d]cyclohepten-13-one (12.0 g.), dry ether (500 ml.), and lithium aluminium hydride (4.0 g.) is refluxed and stirred for 6 hours. The mixture is cooled and then cautiously treated with water, filtered and the residue is extracted with boiling methanol. The cooled extracts deposit crystals of ll-morpholino-10-hydroxy 10,11 dihydro 5H dibenzo[a,d] cycloheptene-S-methanol with M.P. 187-188 C.

A mixture of this intermediate product (6.0 g.), water (20 ml.) and sulphuric acid (10 ml.) is heated on the steam bath for 5 hours. The cooled mixture is rendered alkaline and ether-extracted.

Evaporation of the extracts leaves the title product as an oil characterized by its nuclear magnetic resonance absorption spectrum with maxima at 432, 321, 220-270, and 170180 cps.

The hydrochloride salt is obtained as described above and is purified from ethanol-ether to M.P. 260270 C.

EXAMPLE 3 1 l-piperidino- 10,5- (epoxymethano) 10,1 l-dihydro- SH-dibenzo [a,d] cycloheptene In the same manner as described in Example '2, but using ll-piperidino 10,5 (epoxymethano) 10,11 dihydro 5H dibenzo[a,d]cyclohepten-13-one, with M.P. 203205 C., as starting material in place of ll-morpholino 10,5 (epoxymethano) 10,11 dihydro-SH-di- 4 benzo[a,d]cyclohepten-13-one, is obtained ll-piperidino- 10-hydr0xy 10,11 dihydro 5H dibenzo[a,d]cyclohepten-S-methanol with M.P. 200-202 C. when crystallized from methanol.

This intermediate is treated With aqueous sulfuric acid in the same manner as described in Example 2 to give the title product as an oil characterized by its nuclear magnetic resonance spectrum with maxima at 430, 320, 268, 260, 230245, 170, and 92 cps.

The hydrochloric acid addition salt is prepared as described above. It is crystallized from ethanol-ether to M.P. 273277 C.

Using as starting material a geometrical isomer of the above ll-piperidino 10,5 (epoxymethano) 10,11 dihydro-SH-dibenzo[a,d]cyclohepten 13 one, with M.P. 172-174 C.; there is obtained a geometrical isomer of the title product. It is purified from ethyl acetate to M.P. 122-125" C. and is further characterized by its nuclear magnetic resonance spectrum with maxima at 435, 312, 262, 230-250, 138 and cps.

EXAMPLE 4 1 1-(N'-methylpiperazino)-10,5-(epoxymethano) 10,1l-dihydro-SH-dibenzo[a,d]cycloheptene In the same manner as described above, but using 11 (N'-methylpiperazino)-10,5-(epoxymethano)-10,11- dihydro-SH-dibenzo[a,d]cyclohepten-13-one as starting material there is obtained l1-(N'-methylpiperazino)-l0,5- (epoxymethano)-10,1l-dihydro-SH dibenzo[a,d]cycloheptene-S-methanol which is purified from benzene to M.P. 187189 C.

This compound is cyclized With sulfuric acid in the same manner as described above to give the title product as an oil characterized by its nuclear magnetic resonance absorption spectrum with maxima at 430, 319, 267, 259, 23 l244, 170-179, -450, and 147 cps.

The dihydrochloric acid addition salt is prepared as described above and is purified from ethanol to M.P. 240-250 C.

In the same manner, but using 11-(N'-phenylpiperzino)-10,5-(epoxymethano)-10,1I-dihydro 5H dibenzo [a,d]cycloheptene-13-one as starting material, the corresponding 11-(N'-phenylpiperazino)-10,5-(epoxymethano)- 10,1l-dihydro-SH-dibenzo[a,d]cycloheptene is obtained.

In the same manner, but using the corresponding 11- pyrrolidino derivative as starting material, ll-pyrrolidino- 10,5 (epoxymethano) 10,11 dihydro 5H dibenzo [a,d]cycloheptene is obtained.

EXAMPLE 5 In a similar manner to that described in Examples 14 but using as starting material 11-diethylamino-, ll-dipropylamino-, 11-dibutylamino-, 11-dipentylamino-, 11- dihexylamino-, 1l-(N-methylpropylamino)-, (ll-(N-butylpentylarnino)-, 11 (N-ethylhexylamino}, ll-(N- methylbenzylamino)-, or 11-(N-propylphenethylamino)- 10,5 (epoxymethano)-10,11 dihydro-5H-dibenzo[a,d] cyclohepten-13-one the corresponding 11-diethylamino-, 11-dipropylamino-, 1l-dibutylamino-, 11-diphenylamino-, 11-dihexylamino-, 1I-(N-methylpropylamino)-, 11-(N- butylpentylamino), 11 (N-ethylhexylamino)-, ll-(N- methylbenzylamino)-, or 11-(N-propylphenethylamino)- 2. 1l-dimethylamino-10,5-(epoxymethano) 10,11 dihydro-H-dibenzo[a,d]cycloheptene, as claimed in claim 1.

3. The hydrochloride salt of 1l-dimethylamino-10,5- (epoxymethano)-10,ll-dihydro-SH dibenzo[a,d]cycloheptene, as claimed in claim 1.

4. The process of preparing a compound of the formula wherein R and R each represent lower alkyl, which comprises subjecting a compound of the formula R and R being as above defined, in an inert solvent to the action of an alkali metal aluminium hydride; adding water to the resulting reaction mixture in order to eifect hydrolysis of the intermediate complex, thereby securing a compound of the formula R and R being as above defined; treating said last-named compound with a molar excess of aqueous mineral acid at an elevated temperature above room temperature; and then adding an alkaline agent to said reaction mixture in amount sufiicient to render said reaction mixture alkaline in reaction, thereby obtaining said desired compound.

5. The process, as defined in claim 4, which comprises subjecting said compound of formula in which R and R are as defined above, to the action of 5 lithium aluminium hydride in an inert solvent at a temperature Within the range 30-100 C.; adding Water to the resulting reaction mixture in order to eifect hydrolysis of the intermediate complex, thereby securing said compound of formula in which R and R are as defined above; heating said last-named compound with a molar excess of aqueous sulfuric acid of 10 to 50 percent concentration at a temperature within the range 50l00 C.; and adding an alkaline agent to the resulting reaction mixture in amount sufficient to render said reaction mixture alkaline in reaction, thereby securing said desired compound.

References Cited Dobson et al.: Tetrahedron Letters, No. 42 (1967) pp. 4139-42.

ALEX MAZEL, Primary Examiner J. H. TURNIPSEED, Assistant Examiner US. Cl. X.R.

22 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,535, 340 Dated October 20, 1970 Inventor) Thomas A. Dobson and Martin A. Davis It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Claim 1, below the formula, insert ---wherein R and R each represent lower alkyl; and acid addition salts of said compounds with pharmacologically acceptable acids.-

Signed and sealed this 28th day of September 1971 (SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Acting Commissioner of Patents 

